Catechol-O-Methyltransferase Inhibitors in the Management of Parkinson's Disease

ABSTRACT

Parkinson's disease is the most common neurodegenerative disease in which the chemical pathology is known and effective symptomatic treatment, levodopa, is available. Therapy in the initial years after initiation with dopa decarboxylase inhibitors, carbidopa or benserazide, combined with levodopa results in favorable, stable responses. However, by 5 years after the initiation of treatment, over two thirds of patients experience motor fluctuations beginning initially with a ``wearing-off'' effect followed by more complex fluctuations including dyskinesias and ``on-off'' responses. A number of strategies have been developed in an attempt to deal with these complications including changing doses and frequencies, adding agonist medications, adding or substituting controlled-release levodopa, and surgical therapies. A more recent strategy has centered on increasing the availability of intracellular levodopa and synaptic dopamine by inhibiting the peripheral and central metabolism of levodopa to 3-O-methyldopa with the use of a catechol-O-methyltransferase inhibitor. To date, two of these inhibitors, tolcapone and entacapone, are available to treat the wearing-off phase of levodopa therapy.

KEYWORD

COMT inhibitors - entacapone - tolcapone

REFERENCES

• 1 Brooks D J. PET: its Clinical Role in Neurology.  J Neurol Neurosurg Psychiatry . 1991;  54 1-4
• 2 Hornykiewicz O. Biochemical aspects of Parkinson's disease.  Neurology . 1998;  51(suppl. 2) S2-S9
• 3 Marsden C D, Parkes D. Success and problems of long-term levodopa therapy in Parkinson's disease.  Lancet . 1977;  1 345-349
• 4 Juncos J L. Levodopa: pharmacology, pharmacokinetics and pharmacodynamics.  Neurol Clin . 1992;  10 487-509
• 5 Obeso J A, Linazasoro G, Gorospe A. Complications associated with chronic levodopa therapy in Parkinson's disease. In: Olanow CW, Obeso JA, eds. Beyond the Decade of the Brain Vol 2. Dopamine Agonists in Early Parkinson's Disease Kent, UK: Wells Medical 1997: 11-35
• 6 Kaakkola S, Gordin A, Mannisto P. General properties and clinical possibilities of new selective inhibitors of catechol-O-methyltransferase.  Pharmacology . 1994;  25 813-824
• 7 DaPrada M, Borgulya J, Napolitano A. Improved therapy of Parkinson's disease with tolcapone and central COMT inhibitors with a S-adenosyl-L-methionine sparing effect.  Clin Neuropharmacol . 1994;  S26-S37 (S26-S37)
• 8 Martinez-Martin P, Obrien C. Extending levodopa action: COMT inhibition.  Neurology . 1998;  S27-S32 (S27-S32)
• 9 Zurcher G, Dingemane J, DaPrada M. Potent COMT inhibition by RO40-7592 in the periphery and in the brain: preclinical and clinical findings.  Adv Neurol . 1993;  60 641-647
• 10 Jorga K. Pharmacokinetics, pharmacodynamics and tolerability of tolcapone: a review of early studies in volunteers.  Neurology . 1998;  S31-S38 (S31-S38)
• 11 Waters C, Kurth M, Bailey P. Tolcapone in stable Parkinson's disease: efficacy and safety of long term treatment.  Neurology . 1997;  49 665-671
• 12 Rajput A, Martin W, Saint-Hilare M-H. Tolcapone improves motor fluctuation in parkinsonian patients with the ``wearing-off'' phenomena.  Neurology . 1997;  49 1066-1071
• 13 Keranen T, Gordin A, Harjolav P. The effect of catechol-O-methyltransferase inhibition by entacapone on the pharmacokinetics and metabolism of levodopa in healthy volunteers.  Clin Neuropharmacol . 1993;  16 145-156
• 14 Ruottinen H M, Rinne U K. Entacapone prolongs levodopa response in a one month double blind study in parkinsonian patients with levodopa related fluctuations.  J Neurol Neurosurg Psychiatry . 1996;  60 36-40
• 15 Rinne U K, Larsen J P, Siden A. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations.  Neurology . 1998;  51 1309-1314
• 16 Parkinson's study group. Entacapone improves motor fluctuations in levodopa treated Parkinson's disease patients.  Ann Neurol . 1997;  42 747-755
• 17 Kurth M, Adler C. COMT inhibition: a new treatment strategy for Parkinson's disease.  Neurology . 1998;  S3-S14 (S3-S14)
• 18 Goetz C. Influence of COMT inhibition on levodopa pharmacology and therapy.  Neurology . 1998;  S26-S30 (S26-S30)
• 19 Luer R. Interventions to achieve tonic exposure to levodopa: delaying or preventing the onset of motor complications.  Pharmacotherapy . 1999;  19 169S-179S
• 20 Bass H, Beiske A G, Ghika J. Catechol-o-methyltransferase inhibition with tolcapone reduces the ``wearing off'' phenomena and levodopa requirement in fluctuating parkinsonian patients.  J Neurol Neurosurg Psychiatry . 1997;  63 421-428